The general objective of the proposed research continues to be to examine whether serotonergic nerve afferents differentially influence corticotropin releasing factor (CRF)-containing neurons that mediate endocrine, autonomic and cardiovascular responses to stressful stimuli. By virtue of its central nervous system (CNS) distribution and actions, CRF is suspected to be a physiological mediator of stress-induced ACTH secretion, adrenomedullary epinephrine release, and cardiovascular activation. Both In vivo and in vitro studies demonstrate stimulatory effects of serotonin on those CRF-containing neurons controlling the pituitary. Recent experiments In my laboratory provide evidence that serotonergic influences are likewise stimulatory to CRF-containing neurons regulating adrenomedullary and cardiovascular function. The proposed studies will first examine whether serotonin acts at a single CNS site or different CNS sites to modulate CRF release and thereby elicit ACTH secretion, epinephrine release and cardiovascular activation. Second, upon identification of the CNS site(s) of action, detailed studies will be performed to define the receptor subtype mediating the stimulatory effects of serotonin on CRF release. Third, experiments are proposed to assess the ability to alter endocrine, sympathoadrenal and cardiovascular responses to stressful stimuli by injecting serotonin antagonists into the identified site(s) of action. The potential significance of these studies relates to increased understanding of the neurochemical regulation of CRF pathways and thus of the CNS organization underlying integrated responses to stressful stimuli. The health relevancy is overt In that stress Is thought to be a predisposing and/or exacerbating factor in a wide Variety of diseases ranging from cardiovascular disorders to immune dysfunction. it Is hoped that these studies ultimately will lead to useful strategies for counteracting the deleterious consequences of stressful events and/or lifestyles.